La genetica della Depressione: i nuovi approcci metodologici

Review

Marina Mitjans1 The genetics of depression: What
Bárbara Arias1, 2
information can new methodologic
approaches provide?
1 2
Unitat d’Antropologia Centro de Investigaciones Biomédicas en Red de Salud Mental
Departament de Biologia Animal (CIBERSAM)
Facultat de Biologia i Institut de Biomedicina (IBUB) Instituto de Salud Carlos III
Universitat de Barcelona

Major depressive disorder is a genetically complex de la depresión mayor. En muchos estudios se han identificado
disease involving several minor, or susceptibility, genes una o varias regiones génicas cuya variabilidad confiere un
whose expression may be modulated by many environmental riesgo pequeño para desarrollar un trastorno depresivo; es de-
factors. From the classical early linkage studies to the cir, dichas variantes explicarían un porcentaje muy pequeño
complete genome-wide association (GWA) study del componente genético total de la enfermedad en la pobla-
methodologies, it is evident that it is difficult to understand ción y, por tanto, poseerían un valor predictivo bajo. Aunque
the genetic bases of this mental disorder. Many studies have los resultados obtenidos hasta el momento no son concluyen-
identified one or more gene regions whose variability confers tes, las nuevas aproximaciones basadas en estudios de inte-
a small risk for developing depressive disorder, explaining a racción gen-ambiente así como los análisis de vías biológicas
small percentage of the total genetic component of disease (basados en los estudios GWAS) abren nuevas y prometedoras
with low predictive value. Although the results to date are perspectivas en la investigación de las bases genéticas y bioló-
inconclusive, new approaches based on gene-environment gicas de la depresión mayor.
interactions and biological pathway analysis (based on GWA Palabras clave:
studies) open new and promising perspectives in the Trastorno depresivo mayor, Factores genéticos de riesgo, Asociación, ligamiento, Interacción
gen-ambiente, GWAS
investigation of the genetic and biological basis of major
depression.
Keywords:
Major depressive disorder, Genetic risk factors, Association, Linkage, Gene-environment
interaction, GWAS

Actas Esp Psiquiatr 2012;40(2):70-83
INTRODUCTION

Major depressive disorder (MDD), or unipolar depression,
La genética de la depresión: ¿qué información is considered a serious mental illness from a medical
aportan las nuevas aproximaciones standpoint. The diagnosis is often complex due to the
metodológicas? difficulty of defining different symptoms and the syndrome
of behaviors and feelings in certain life situations and the
El trastorno depresivo mayor forma parte del grupo de broad clinical variability present in depressive pictures.
enfermedades denominadas genéticamente complejas en Similarly, we should not forget that there are no biological,
cuya base se encuentran involucrados una serie de genes de biochemical or brain morphology markers that allow an
efecto menor o susceptibilidad cuya expresión podría estar unequivocal diagnosis of depression. Due to the absence of
modulada por un gran número de factores ambientales. Desde external markers of depressive disorders, the diagnosis is
los primeros estudios clásicos de ligamiento hasta las nuevas necessarily psychopathological and clinical.1 In this sense,
metodologías de estudio de genoma completo se ha puesto de major depressive disorder is diagnosed based, for example,
manifiesto la dificultad para comprender las bases genéticas on DSM-IV-TR (Diagnostic and Statistical Manual of Mental
Disorders).2 This classification is based on criteria developed
Correspondence: and revised over the past three decades by the American
Bárbara Arias, PhD
Unitat Antropologia, Departament Biologia Animal Psychiatric Association (APA).
Facultat de Biologia. Universitat de Barcelona
Av. Diagonal, 645, 2ª planta According to this categorical diagnosis, major depressive
08028 Barcelona (Spain)
E-mail: barbara.arias@ub.edu disorder is characterized by the presence of a depressed

70 Actas Esp Psiquiatr 2012;40(2):70-83 24

Marina Mitjans, et al. The genetics of depression: What information can new methodologic approaches provide?

Depression can occur at any time in life, most frequently
Table 1 Summary of the symptoms associated between 18 and 44 years of age,6 and with a mean age of
with major depressive disorder
onset of about 27 years.7 The incidence of this disorder in
the population is 10 new cases per 1000 individuals
Symptoms of depression
annually.8
Emotional Depressed mood, sadness
Decreased pleasure or lack of interest in most Epidemiological studies show that, with some exceptions,
activities the prevalence, incidence and morbid risk of depressive
disorder are twice as high in women as in men.9-12 Thus, the
Somatic Weight loss or gain prevalence of this disorder in the general population varies
Insomnia or hypersomnia within a range of 2.6 to 5.5% in men and 6.0 to 11.8% in
Psychomotor agitation or retardation
Fatigue or diminished energy women.13 Other studies that contemplate a broader range of
depression phenotypes have found much higher prevalences,
Cognitive Feelings of worthlessness or excessive or with a range of variation from 10-12% in men and up to
inappropriate guilt 20-25% in women.14, 15
Decreased ability to think or concentrate,
indecision
Recurrent thoughts of death or suicide
GENETICS OF DEPRESSION

Major depressive disorder, like most diseases that affect
humans, is part of the group of diseases known as genetically
mood (hypothymia) and/or loss of interest and diminished
complex diseases, in which both genetic and environmental
pleasure in daily life activities (anhedonia). These symptoms,
factors have a role in the etiology.
which become established and persist over time, interfere
seriously with the daily life of the patient and tend to be The genetic component of these diseases has been
accompanied by somatic or psychological changes and identified from studies in families, twins or adopted children.
abnormalities in different biological functions. These Complex diseases, despite having a genetic basis, do not
symptoms include diminished appetite and weight loss, conform to the classic Mendelian inheritance pattern. In
reduced activity of the individual, constipation, sleep general, the sensitivity threshold model is considered one of
disorders such as hypersomnia or early awakening, agitation the most useful for explaining how the disease is transmitted.
or generalized inhibition of movement, and decreased libido This model assumes that the “disease susceptibility” variable
or loss of libido.3 The depressed person also often exhibits is distributed continuously in the population, so that only
changes in cognitive functions that reduce the capacity to those individuals who surpass a certain threshold manifest
think, concentrate or make decisions. Pessimistic thinking is the disorder. It is hypothesized that a number of minor
also common, often including feelings of guilt and inferiority, effect genes are involved in the origin of this complex
ideas of hopelessness, and recurrent thoughts of death or heredity, whose expression can be modulated by many
suicide. Suicidal ideation should be kept in mind and suicide environmental factors.
attempts are common in people affected by major depression,
with more than 15% of patients ending their lives by
suicide.4
EXISTENCE OF A GENETIC COMPONENT
In order to diagnose a major depressive episode, the
patient must present at least 1 emotional symptom and 4 Family studies
somatic or cognitive symptoms. Furthermore, according to
DSM-IV-TR criteria, these manifestations must be present The first and simplest approach to studying the
for a period of at least 2 weeks. hereditary factors involved in a disorder stems from
observations of the family and study of the prevalence of
According to the World Health Organization (WHO), the disorder in family members, which allow the familial
about 340 million persons currently have depression, but morbid risk of the diagnosis of interest to be calculated.
only 25% of them have access to effective treatment. Consequently, we would start with the hypothesis that the
Depression is one of the five leading causes of disability, prevalence of a particular inherited disorder is higher among
illness and premature death in people between the ages of the relatives of those affected than in the general population
18 and 44 years and it is believed that by 2020 it will be the and that the larger the percentage of genes shared with the
second most important cause of disability, preceded only by affected person, the greater the risk of developing the
cardiovascular disease.5 disorder.



Such studies have confirmed that among the first- In a review by Tsuang and Faraone, approximately 60%
degree relatives of a patient with major depression (parents of the phenotypic variability present in major depression
and siblings have 50% shared genes), there is a significant could be attributed to genetic factors.19 However, in studies
increase in the prevalence of this disease (15%) compared to by other researchers, lower heritability rates situated around
the general population (5.4%).16 40% are observed.20, 21 These differences can be attributed in
part to differences between studies in the definition of the
Family studies, however, have the drawback that they inclusion phenotype.
do not control the environmental factor. We think that
many important aspects of our behavior and psychopathology Most studies of this topic generally show the importance
may be related to behaviors acquired in the family setting of genetic factors and indicate that some of these factors
and are thus equally heritable. In order to complete the might be specific to forms of depression that are particularly
study of the genetic risk factors involved, adoption and twin severe, recurrent and specific to women, whereas other
studies are essential in which it is possible to control the genetic risk factors are shared by individuals of both sexes. 22
environmental factor and differentiate it from the genetic From the perspective of twin studies, early-onset recurrent
factor. depression (before age 30) is the form that accumulates the
greatest genetic risk.23

Regarding the approach to environmental risk factors in
Adoption studies
twin studies, these studies have allowed the investigation of
Different types of adoption studies differ in their how differential studies of certain environmental factors
may explain why in a pair of monozygotic, i.e., genetically
experimental design. The goal is always to determine whether
identical twins, one develops major depressive disorder and
the factors linked to the familial transmission of the disorder
the other does not. Studies by Kendler’s team in a sample of
are biological or environmental.
over 7,000 twins (men and women) have allowed the
In this sense, adoption studies involve comparing the identification of important environmental risk factors for
risk of disease in the biological children of parents with the major depression, such as certain stressful life events,
disorder (high-risk children) who are raised in a healthy specifically those related to loss (death, separation, etc.) and
adoptive family compared to the risk of children of affected humiliation (shameful experiences, separations initiated by
parents raised in their biological family. others).24, 25

Some adoption studies of unipolar depression in children
at high risk of depressive disorder raised in healthy families SEARCH FOR RISK GENES
show higher rates of depression than expected in the general
population,17 which reveals the existence of genetic factors Linkage studies
in the risk of major depression, especially for the most severe
forms of the disease.18 In linkage analysis, genealogies in which the disease
occurs in different family members and in which there is a
Mendelian inheritance pattern are usually used. In these
Studies of twins families, the segregation of a particular genetic marker is
studied to determine if disease transmission and different
Studies of twins allow the relative importance of genes, alleles of this marker show independence. Where the
the environment, and the interaction between them to be disease and a given allele are transmitted together, this
estimated in relation to certain complex characteristics of may suggest the existence of a gene for disease located
human beings. near the polymorphism used as a marker.

These studies compare the concordance rates for a given These studies allow the LOD-score to be calculated.
disorder in monozygotic, or identical, twins (who share all This statistical parameter tells us the likelihood of genetic
their genes) and in dizygotic twins (who share only half their linkage between the genetic marker studied and the
genes), which allows the relative contribution of genes and disease, i.e., the probability that they are transmitted
together (LOD-score> 3).
environment in the origin of these mental disorders to be
evaluated. The comparison of the concordance between the Such studies have been relatively numerous in the
two types of twins used to assess the heritability (h2) of the genetic investigation of mental disorders, but the lack of a
disorder is a statistical measure of the degree to which genes Mendelian model of inheritance of these disorders, suspected
contribute to the total variability observed in a character or etiological heterogeneity, involvement of environmental
phenotype. factors in their diagnosis and the phenotypical heterogeneity



Table 2 Linkage studies in major depression and subtypes (recurrent and early-onset recurrent)
(table adapted from Middledorp et al.26)

Chromosome Region (cM) LOD N subjects/families Phenotype Reference

1 42 1.7 426/90 MDD-RE 27

2 90.6 1.7 ?/278 MDD 26

237-248 2.2 224 possible pairs MDD (+alcohol) 31

2.5b ?/81 MDD 32

15 319 ?/81 MDD-RE 91

8 2.7 1.9 ?/278 MDD 26

10 5-9 1.6 426/90 MDD-RE 27

76 3.0 ?/81 MDD 32

11 85-99 2.5 ?/81 MDD 32

12 105-124 1.6 994/497 R-MDD 30

17 17q11.2 2.1 ?/278 MDD 26

18 73 3.8 96/21 MDD-RE & anxiety 27

LOD> 3 = Linkage, -2 <LOD <3 = inconclusive; LOD <-2 = No linkage
MDD: major depressive disease
MDD-RE: major depressive disease, recurrent early-onset (age at onset <31)
MDD-R: major depressive disease, recurrent

are, among others, reasons that might explain the Another interesting result is found in chromosomal
inconclusive results obtained to date.26 region 17q11.2, in which a study with a sample of patients
The most important linkage studies conducted in with MDD found an LOD-score of 2.1.26 This chromosome
major depressive disorder are summarized in Table 2. region harbors the serotonin transporter gene (SLC6A4),
which has gained prominence in gene-environment
Among the analyses carried out in major depression
interaction (GxE) studies, which will be discussed later in
are linkage studies that have made it possible to identify
candidate genes for this disorder.27-32 One of the most this chapter.34
interesting findings involves chromosome 11. The study,
A recent study has shown evidence of linkage with the
conducted in samples with recurrent major depression,
found an LOD-score of more than 3 (4.2) in the 11pter-p15 2q33.34 chromosomal region found in the CREB1 gene in
chromosomal region.32 This result was partially replicated women with early-onset recurrent major depression.32 This
by a second study that obtained an LOD-score of 1.6 in the gene encodes for the CREB1 transcription factor that
same chromosomal region.27 Interestingly, this region of regulates the expression of growth factors involved in
chromosome 11 contains genes that have been considered
synaptogenesis and neurogenesis, which makes it a good
candidates for MDD, such as tyrosine hydroxylase (TH), a
key enzyme in dopamine synthesis. In fact, some studies candidate in view of the hypothesis that alterations in the
have shown that TH inhibition can cause depressive cellular pathways involved in synaptic plasticity contribute
symptoms in healthy subjects.33 to increasing the risk of developing depression.35



Linkage studies, although not the most powerful neurotransmission pathways, especially serotonergic
methodology for detecting genes involved in complex neurotransmission.38
diseases such as MDD, have been useful in detecting regions
containing genes that have been subsequently implicated in In this sense, the SLC6A4 gene has been one of the
the origin of the disease by association studies or GxE genes most studied because it encodes the protein that is a
interaction studies. therapeutic target of selective serotonin reuptake inhibition
drugs. This gene (chromosome 17q11.1-Q72) encodes the
serotonin transporter and has a polymorphism (5-HTTLPR) in
Association studies the promoter region, with two allelic variants: 528 (L) and
484 (S). Studies in vivo have determined that the presence
Analysis of genetic associations is an alternative to of the short 484 allele was associated with decreased gene
linkage studies and one of the best strategies for identifying expression and, consequently, with fewer serotonin transporters
the genes responsible for genetically complex diseases in in the neuronal membrane.39-41 Likewise, various association
which there is no known inheritance model, in which many studies have described the relationship between the presence
genes with minor effects are probably involved. of the short allele of the 5-HTTLPR polymorphism and the
presence of depression severity traits (suicide or melancholy)42-43
The classic design of a genetic association analysis is a and increased vulnerability to develop major depression when
case-control study in which the frequency of a possible risk the person has been abused in childhood.42, 44, 45
allele of a candidate gene in unrelated individuals affected
by the same disease (case group) is compared to the Similarly, when considering serotonergic neurotrans-
frequency observed in healthy individuals of the same ethnic mission, other studies show an association between other
group (control group). If the risk factor analyzed is found genes of the serotonergic neurotransmission system and the
more frequently in the case group than in controls, an presence of depression severity traits such as seasonality46, 47
association exists between the factor and the disease. This or suicide.48, 49 However, the identification of genetic vari-
means that the exposure, or presence, of this factor increases ants of interest, or relatively specific genetic variants related
the risk of, or susceptibility to, the disease. to the most endogenous forms of depression, remains to be
established.
In genetic association studies, the risk factor analyzed is
always a genetic marker or polymorphism, usually located
on a candidate gene for the disease. The results are reported Gene-environment interaction (GxE) studies
as an odds ratio (OR), which indicates how much more
common the disease is in carriers with genetic variants of Analysis of the gene-environment relation opens new
risk than in non-carriers. perspectives for understanding the etiology of major
depression, in which the genetic profile of a person and its
Since the first case-control study conducted by Beckman continuous interaction with the environment are the focus
et al. linking major depression and genetic variability,36 a of study. This interaction could be explained by genetically
large number of studies have been published, but few mediated sensitivity to the environmental factors to which a
susceptibility genes for the origin of depression have been person is exposed throughout life. This means that certain
recognized and replicated. genotypes (risk genotypes) confer a higher probability of
suffering the disorder than others (non-risk genotypes),
These inconsistent results may be due to methodological
given the same exposure to an environmental risk factor.
differences between studies, such as the study design, study
According to this model, individuals differ in their sensitivity
population, diagnosis of major depression or even the lack
to adverse environmental factors, so that genetically
of statistical power due to a small sample size.37
vulnerable persons are at increased risk of developing the
A meta-analysis of genetic association studies in major disease when exposed to the same dose of a particular
depression was recently conducted in which 20 environmental risk factor.50
polymorphisms in 18 genes were analyzed. Five of these
In 2003, a paradigmatic study was published in the
genes showed a statistically significant association with
search for gene-environment interactions in the origin of
major depression (APOE, GNB3, MTHFR, SLC6A3 and
SLC6A4).37 The results of this meta-analysis are summarized depression. Caspi’s team showed that individuals carrying
in Table 3. the short allele (S) of the 5-HTTLPR polymorphism of the
serotonin transporter gene had experienced stressful life
events in childhood and youth, and presented more
Most researchers have focused on genes encoding depressive symptoms, depressive episodes and suicidal
proteins that are involved in central nervous system behavior at age 26.34


29
Table 3 Meta-analysis of genetic association studies in major depression. (Table adapted from López-León et al..37)

Heterozygotes Homozygotes
Marina Mitjans, et al.

Gene Region Polymorphism Studies Analysis Comparison OR (95% CI) I2 Comparison OR (95% CI) I2

ACE (angiotensin I Ins/Del –Int16 8 Fixed IV vs II 0.94(0.78-1.13) 27 DD vs II 1.15 (0.94-1.42) 26

converting enzyme) 17q23.3 Random 0.90 (80.71-1.13) 1.11 (0.85-1.45)

APOE 19q13.2 ɛ2/ ɛ3/ ɛ4 5 Fixeds ɛ2/ɛ3 vs ɛ3/ɛ3 0.42 (0.28-0.62)*** 72* ɛ2/ɛ2 vs ɛ3/ɛ3 NA

(apolipoprotein E) Random 0.41 (0.15-1.07) NA

5 Fixeds ɛ3/ɛ4 vs ɛ3/ɛ3 1.02 (0.78-1.35) 0 ɛ4/ɛ4 vs ɛ3/ɛ3 1.02 (0.44-2.37) 32

Random 1.02 (0.78-1.35) 0.91(0.25-3.33)

BDNF (brain-derived 11p13 Val66Met 8 Fixeds Val/Met vs 0.98 (0.89-109) 0 Met/Met vs 1.05 (0.84-1.32) 53*

neurotrophic factor) Random Val/Val 0.98 (0.89-109) Val/Val 1.09 (0.72-1.65)

COMT (catechol-O- 22q11.21 Val158Met 6 Fixeds Val/Met vs 1.14 (0.86-1.52) 29 Met/Met vs 0.95 (0.67-1.33)

methyltransferase) Random Val/Val 1.13 (0.86-1.59) Val/Val 0.95 (0.67-1.33) 12

DRD3 (dopamine receptor 3q13.3 Ser9Gly 4 Fixeds Ser/Gly vs 0.92 (0.67-1.26) 33 Ser/Ser vs 1.31 (0.80-2.14) 72*

D3) Random Ser/Ser 0.96 (0.64-1.45) Ser/Ser 1.71 (0.57-5.13)

GABRA3 (gamma- Xq28 CA repeat 6 Fixeds */1 vs 1/1 0.74 (0.49-1.12) 46 */* vs1/1 0.92 (0.40-2.11) 10
aminobutyric acid A

receptor. alpha 3) Random 0.63 (0.32-1.25) 0.97 (0.36-2.62)

GNB3 (guanine nucleotide 12p13 C825T 3 Fixeds CT vs CC 1.25 (0.91-1.72) 50 TT vs CC 2.13 (1.39-3.28)** 67*
binding protein beta

polypeptide 3) Random 1.30 (0.81-2.09) 2.09 (0.97-4.51)

HTR1A (5-hydroxytryptamine 5q11.2-q13 C-1019G 4 Fixeds CG vs CC 0.98 (0.72-1.33) 18 GG vs CC 1.33 (0.95-1.87) 79**

receptor 1A) Random 0.98 (0.69-1.38) 1.63 (0.72-3.70)

HTR1B (5-hydroxytryptamine 6q13 G861C 3 Fixeds GC vs GG 0.99 (0.74-1.33) 42 CC vs GG 0.81 (0.46-1.41) 25

receptor 1B) Random 0.98 (0.66-1.44) 0.79 (0.41-1.53)
The genetics of depression: What information can new methodologic approaches provide?

HTR2A 13q14-q21 A-1438G 4 Fixeds AG vs AA 1.23 (0.88-1.73) 62* GG vs AA 1.06 (0.73-1.55) 75**

75

76
Table 3 Continuated

Heterozygotes Homozygotes
Marina Mitjans, et al.

Gene Region Polymorphism Studies Analysis Comparison OR (95% CI) I2 Comparison OR (95% CI) I2

(5-hydroxytryptamine Random 1.15 (0.65-2.03) 0.98 (0.45-2.14)

receptor 2A) T102C 8 Fixeds TC vs TT 1.00 (0.79-1.27) 0 CC vs TT 0.92 (0.71-1.21) 17

Random 1.00 (0.79-1.27) 0.92 (0.68-1.25)

MAOA (monoamine Xp11.3 VNTRprom 4 Fixeds 12 vs 22 1.34 (0.95-1.89) 17 11 vs 22 0.71 (0.49-1.02) 0

oxidase A) Random 1.29 (0.87-1.91) 0.71 (0.49-1.03)

MTHFR 1p36.3 C677T 6 Fixeds CT vs CC 1.22 (1.03-1.44)* 26 TT vs CC 1.38 (1.08-1.76)* 0

(methylenete- Random 1.23 (0.95-1.58) 1.38 (1.08-1.77)*
trahydrofolate reductase)

SLC6A2 (noradrenalin 16q12.2 T-182C 3 Fixeds TC vs TT 1.21 (0.91-1.61) 52 CC vs TT 0.72 (0.45-1.14) 64

transporter 2) Random 1.23 (0.81-1.85) 0.75 (0.33-1.67)

SLC6A3 (DAT1) (dopamine 5p15.3 40bp VNTR 3 Fixeds 9/10 vs 10/10 2.06 (1.25-3.40)** 0 9/9 vs 10/10 1.46 (0.67-3.16)

transporter 3) Random 2.05 (1.24-3.40)** 1.47 (0.67-3.19)

SLC6A4 (SERT) 17q11.2 44bp Ins/del 22 Fixeds LS vs LL 1.05 (0.94-1.18) 0 SS vs LL 1.39 (1.20-1.61)** 0

(serotonine transporter 4) Random 1.05 (0.93-1.18) 1.39 (1.20-1.61)**

VNTR-In2 8 Fixeds 10/12 vs 12/12 0.94 (0.74-1.20) 24 10/10 vs 12/12 1.17 (0.82-1.68) 0

Random 0.98 (0.73-1.32) 1.18 (0.82-1.70)

TPH1 (tryptophan 11p15.3-p14 A218C 9 Fixeds AC vs AA 1.10 (0.91-1.34) 49 CC vs AA 0.88 (0.71-1.09) 35

hydroxylase 1) Random 1.14 (0.85-1.52) 0.86 (0.65-1.14)

TAll the studies used random and/or ﬁxed effects meta-analysis methods.
OR, odds ratio CI, 95% conﬁdence interval.
The references of these studies can be found in the review by López-León et al.37
The genetics of depression: What information can new methodologic approaches provide?

30


Although several authors had postulated that stressful especially in individuals with high genetic vulnerability, and
situations involving sense of defeat, loss, humiliation and thus increase the risk of suffering a disorder of the depressive
frustration influence the age at onset of depression,51-54 the spectrum in adulthood.
Caspi study team was the first to demonstrate this GxE
interaction empirically.34 Given the complexity of the depressive phenotype, not
only the approaches based on genetic association or GxE
However, the debate about the role of this polymorphism interaction studies help to explain the origin of this disease.
in the risk of depression is evident in the recent literature. A Other approaches based on epistatic or gene-gene interaction
meta-analysis by the team of Risch et al. concluded that life (GxG) models should also be considered. In this sense, it
events have a strong relation with the increased risk of should be noted that the action of a gene can be modified
major depression. However, the addition of genetic variability by that of one or more other genes (modifiers), i.e., the
associated with the serotonin reuptake gene does not appear phenotypic consequences of an allele generally depend on
to increase the predictive power of negative life events per multiple alleles with a complex interaction.
se on the risk of major depression.55 The results obtained
from this meta-analysis show the same tendency as the
study by Munafo et al., in which it is concluded that the Genome-wide association (GWA) studies in
associations found to date could be consistent with random depression. Is this approach valid?
results.56 Despite the results obtained, a new study supports
the existence of an interaction between the serotonin One of the most recent methodologies used in the
transporter gene and major depression initially found by search for genetic risk factors in complex diseases is based
Caspi et al.34 The authors of this meta-analysis57 show that on genome-wide association (GWA) studies. This methodology
the results of two previous meta-analyses did not take into is based on genotyping arrays or microarrays that allow the
account all the published studies, so their results are not variability of the human genome (up to a million genetic
valid. markers in a subject in a single text) to be traced in order to
assess the hypothesis of common disease-common variant
It should be noted that, despite the data collected in without the need to conduct a hypothesis-guided study of
these studies, not all people who experience stressful events the etiology of the disease.
develop depression. This may be related to the genetic
substrate of vulnerability. In this sense, this hypothesis is Currently, GWA studies unguided by hypotheses are
supported by the genetics of behavior, since it has been transforming our understanding of the genetic and
documented that the risk of depression after a stressful pathophysiological architecture of complex medical
event is higher among individuals who are in a group at high conditions. Since 2005, nearly 100 genetic risk variants have
familial genetic risk than in those who do not exhibit this been replicated in up to 40 common diseases, such as
increased genetic risk.58 diabetes or cancer. Many of these variants are found either
in genes that were not previously considered candidates for
In this sense, early traumatic experiences like child abuse disease, or in genomic regions that do not contain genes.68
have been described as one of the most important Similarly, promising results have been found in disorders
environmental risk factors leading to the onset of major with a low prevalence and high heritability, such as Crohn’s
depression in adults.58-60 Evidence from neurobiology and disease.69
epidemiology suggests that disruptive adverse events that
occur during an individual’s development can cause persistent With regard to GWA studies in MDD, the first study was
cerebral dysfunction.61, 62 The impact of such events on brain developed by Muglia et al. in 2008, in two independent
neurobiology would be moderated by individual genetic samples of recurrent major depression: the first consisting
variability and the literature indicates that both the gene of 1022 patients diagnosed of recurrent major depression
encoding the serotonin transporter34, 63 and the gene encoding and 1000 controls and the second consisting of 492 patients
brain-derived neurotrophic factor (BDNF)64, 65 seem to play a diagnosed of the same disease and 1052 controls.
key role in modulating the impact of childhood abuse and the Unfortunately, no significant results were obtained in any of
risk of the emergence of depressive symptoms in adulthood.66 the samples used, meaning that none of the polymorphisms
Thus, early experiences can affect the development of the examined showed an association with the phenotype with a
hypothalamic-pituitary-adrenal (HPA) axis and neurobiological p-value below the limit of significance established in GWA
responses to stress in adulthood, and predispose the individual studies (p<10-8). In order to increase statistical power, the
to the development of MDD.67 authors made a meta-analysis of the two studies in which
the results confirmed those obtained by the two previous
Such studies help to understand how early life stressors independent analyses. According to the findings, the authors
can leave an indelible mark on the central nervous system, suggest the possibility that there is no genetic marker that



provides a significant OR for major depression per se, the three largest GWA studies of MDD). No polymorphism
understood from a categorical diagnosis.70 reached genome-wide significance in either the study itself
or in the meta-analysis, with a total of 5763 cases and 6901
In this regard, in a study made after this GWA study in controls. These results imply that either common variants of
1738 patients with early-onset (onset before age 31) intermediate effect do not seem to have important effects
recurrent depressive disorder and 1802 controls, no on the genetic architecture of major depression,76 or that
significant association was found in relation to established the phenotypic heterogeneity of the disease impedes the
statistical parameters for GWA studies.71 However, marginal detection of overall genetic risk factors.
significance was observed in chromosomal region 18q22.1
(rs17077540, p=1.83*10-7). Previous studies have shown the GWA studies have undoubtedly opened a new door in
existence of a genetic association between this region and the investigation of the importance of genetic factors in the
major depressive disorder.38 This region is approximately 75 origin of depression. However, we must be aware that some
Kb from the DSEL (dermatan sulfate epimerase-like) gene, a genes may be associated with the disease (as demonstrated
gene expressed in the brain with unknown function, in which in classic association studies) without attaining the level of
two non-synonymous mutations were observed in patients significance required in a genome-wide association study.
with bipolar affective disorder but not in controls. 72 This means that we must take into account that, while the
analysis of individual SNPs has been useful in identifying
In the same line, a new GWA study (GAIN MDD) achieved variants of disease-related susceptibility, this mode of
significant results, in which the signals of maximum analysis can be quite limiting in certain situations because
significance were detected over the region of the of the difficulty of achieving the levels of significance
chromosome 7 gene occupied by the Piccolo (PCLO) gene, established in genome-wide association studies. Specifically,
whose protein is located in the presynaptic active zone and for the purpose of controlling type I errors, the statistical
cytomatrix and is important in serotonergic neurotransmission. level of each test must be adjusted. Due to the large number
Two SNPs (single nucleotide polymorphisms) showed of hypotheses considered, the threshold of significance for
maximum significance values: rs2715148 (p=7.7*10-7) and GWA studies can be extreme and difficult to attain.
rs2522833 (p=1.2*10-6),73 but only the second could be Remember that for a GWA study analyzing the effect of
replicated in independent samples that were phenotypically 500,000 SNPs, each statistical test is performed at a significance
similar to the first sample. Recently, this association with the level of at least 10-8, which is highly restrictive.77 The small
PCLO gene rs2522833 polymorphism has been confirmed in p-value of GWA studies thus requires a sample size on the
an independent sample of depressed patients of Dutch order of thousands of subjects to achieve sufficient statistical
origin.74 power to allow the detection of polymorphisms in genes
with a minor effect. The need for inclusion of a sample of
Another GWA study (UK study) conducted by the Lewis
this size is related to the greater heterogeneity of the
team of in a sample of 1636 patients with recurrent major
samples due to inclusion criteria variability between
depression and 1594 control subjects showed evidence of an
evaluators and/or sites or the use of broader inclusion
association between an SNP polymorphism in the BICC1
criteria to ensure an adequate sample size. It would be
gene (bicaudal C homologue 1 gene).75 The product of this
desirable to have large samples with a restrictive or extreme
gene, expressed in all brain regions, is an RNA binding phenotype to reduce sample variability. The working
protein that forms complex interactions with RNA and other definition of the phenotype is a prerequisite for successful
proteins. The association of BICC1 and depression is a novel genetic studies.78
finding since no previous evidence existed of the role of this
gene in neuropsychiatric diseases. This association was In summary, the results of GWA studies suggest that we
stronger when analyzed in a population of women diagnosed are far from being able to identify the genes responsible for
of depression.75 Various interesting signs of association were the diseases studied. Many studies have identified one or
identified but, as in previous genome-wide association more gene regions that confer a small risk, which indicates
studies, it was suggested that the contributions of individual that there is only a small percentage of total genetic
genes to major depression may be only minor.75 component of the disease in the population and that it has
a low predictive value.
The recent MDD2000+ study conducted by the team of
Wray et al. is the largest GWA study of major depression
reported to date, with 2431 cases of MDD and 3673 controls. 76 CONCLUSIONS
This group compared their results to those published on
other GWA studies of major depression.73, 75 In this study, a Depression undoubtedly has a complex and
meta-analysis was also made of autosomal SNPs with the heterogeneous phenotype in terms of its biology and
samples of the MDD200+, GAIN MDD73 and UK studies75 (i.e., etiology, in which both genetic and environmental factors



play a fundamental role. In this sense, from the vantage possible solutions proposed are related to both genetic and
point of quantitative genetics, family and twin studies have methodological issues that are poorly controlled in current
confirmed the importance of genetic factors and suggest designs. Among the genetic issues per se are trait penetrance,
that depressive disorder, like other common mental illnesses, i.e., the frequency with which a trait or phenotype is
is a complex condition that reflects the influence of many expressed when a specific gene combination is present, the
genes with a minor effect. Likewise, we must not forget that existence of epistasis and epigenetic processes, the genetic
understanding any complex characteristic of human beings heterogeneity of the disease, the presence of undetected
is impossible without simultaneously considering the effect rare variants with more penetrance (a less common allele
of genes and environment, environment being understood with a frequency of at least 1%), or even the existence of an
in its broadest sense, as a factor in continuous interaction incomplete linkage imbalance between the SNP marker and
with individual genotype. true causal variants.

Molecular studies have helped to establish the genetic On the other hand, among the methodological issues,
basis of disease more specifically. Among them, the classic possible errors in genotyping should be taken into account,
linkage studies have made it possible to identify chromosomal including copy number variations (CNV) and the control of
regions at risk and, thus, to identify some candidate genes GxE interactions.80-87 However, how a complex trait is
by their genomic position and function. Similarly, association measured and how phenotypic information is used are just
studies have shown that a certain degree of genetic as important as the correct detection of genetic variants.88 A
variability, particularly associated with genes of the stricter redefinition of phenotype could, a priori, increase
serotonergic system, seems to contribute to the risk of the power to detect more robust effects.
disease and certain clinical aspects of the disease, such as
the clinical response to pharmacological treatment with In addition, we must not forget that the search for
antidepressants.79 statistically significant associations between a genetic
polymorphism and mental illness is just the first step in
Interestingly, GxE interaction studies have shown the understanding the role of genetic variants in the pathogenesis
importance of environment in the risk of developing MDD. of the disease. The next step involves knowledge of the
In the literature, evidence had already been found that the functional effect of these genetic variants and how they act
presence of stressful life events in the course of life, such as in the expression of disease phenotype.
feelings of defeat, loss, humiliation and frustration, or child
abuse, increased the risk of MDD.51-54 However, these studies We can conclude that GWA studies are still in their
revealed that the impact of these adverse events on the infancy and new approaches are being perfected to improve
neurobiology of the brain is moderated by certain individual the performance of the vast amounts of data provided by
genetic variability, as was demonstrated in the study by this analysis. One option proposed would be to conduct a
Caspi et al. mentioned above.34 meta-analysis in which all the information from multiple
GWA studies is pooled, thus increasing the chances of finding
Finally the results of GWA studies in disorders with a true positives among the false positives. A second approach
high prevalence and lower heritability, such as major is to search for epistasis in each GWA study to identify more
depressive disorder, present a more complicated challenge robust results that would appear when gene-gene
when analyzing the results. These are expensive studies that interactions are taken into account. Finally, one of the most
have not yet met expectations in the field of mental illness. interesting options would be to prioritize certain genes and
For instance, although the results of GWA studies have alleles using information from known biological pathways
identified candidate genes for depression, as of yet it has [89]. In this sense, GWA study pathway analysis (GWASPA)
not been possible to replicate the association of specific seems to be the next step in understanding the genetic basis
candidate genes previously identified by classical association of complex diseases.90 These new approaches focus on
studies. examining a collection of predefined genes based on
available biological knowledge of the genes and their
Consequently, these early GWA studies have generated possible implication in the disease. It is well known that
a number of important questions regarding the genetic genes do not function in isolation. They generally form part
variants identified to date. In first place, the results of GWA of complex molecular networks and different cellular
studies raise the issue of “missing heritability” as a serious pathways that are frequently involved in susceptibility and
problem in GWA study design. Missing heritability is the disease progression.
difference between the large proportion of the phenotype
of major depression explained by genetic factors, as Although these new approaches configure the near
estimated by heritability studies, and the scant risk genes future of the investigation of the molecular basis of complex
identified by GWA studies. Most of the explanations and disease, there are still many unknowns to be clarified, largely



related to the role of genetic variability and CNVs (copy Psychiatric Association, 2000.
number variants), which are currently not included in GWA 3. Paykel ES. Handbook Of Affective Disorders, Second Edition.
analysis. Likewise, the role of rare structural variants (with 1992.
4. Goodwin FK, Jamison KR. Manic Depressive Illness. New York:
higher penetrance) and their interaction with the common
NY: Oxford Press In, 1990.
type SNP variability is under study.
5. Murray CJL, Lopez AD. Alternative projections of mortality and
Finally, we must not overlook the role of the environment, disability by cause 1990-2020: Global burden of disease study.
Lancet. 1997;349(9064):1498-504.
understood in its broadest sense. GxE interaction studies
6. Zisook S, Lesser I, Stewart JW, Wisniewski SR, Balasubramani
have shown that individuals are probably genetically more
GK, Fava M, et al. Effect of age at onset on the course of
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2004;109:21-7.
The results obtained so far with regard to the genetic 8. Murphy JM, Nierenberg AA, Laird NM, Monson RR, Sobol AM,
risk for major depression are not powerful enough to support Leighton AH. Incidence of major depression: prediction from
predictions that attain the levels of sensitivity and specificity subthreshold categories in the Stirling County Study. Journal of
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